CD20 supports BCR signaling in an intra-clonal aggressive chronic lymphocytic leukemia subpopulation of cells and rituximab primarily targets these BCR-profıcient B cells in vivo

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F18%3A00068872" target="_blank" >RIV/65269705:_____/18:00068872 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14740/18:00104003

Výsledek na webu

<a href="https://cancerres.aacrjournals.org/content/78/13_Supplement/1012" target="_blank" >https://cancerres.aacrjournals.org/content/78/13_Supplement/1012</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1158/1538-7445.AM2018-1012" target="_blank" >10.1158/1538-7445.AM2018-1012</a>

Jazyk výsledku

angličtina

Název v původním jazyce

CD20 supports BCR signaling in an intra-clonal aggressive chronic lymphocytic leukemia subpopulation of cells and rituximab primarily targets these BCR-profıcient B cells in vivo

Popis výsledku v původním jazyce

The hallmark of chronic lymphocytic leukemia (CLL) cells is their re-circulation between peripheral blood and immune niches to obtain pro-proliferative and pro-survival signals. CLL cells that have recently exited the immune niches to the peripheral blood are characterized by low cell-surface levels of chemokine receptor CXCR4 and high levels of activation molecule CD5. These CXCR4dimCD5bright CLL cells have a ~2-fold higher CD20 expression due to the activation of the CXCR4/SDF-1 axis (Pavlasova et al., Blood, 2016). We hypothesized that CD20 up-regulation in the context of a microenvironment is required for some functional regulation. We hypothesized that CD20 expression is of importance for B-cell receptor (BCR) signaling as we observed that CXCR4dimCD5brightCD20bright CLL cells have also ~2-fold higher surface IgM levels (P&lt;0.0001). This was coupled with higher responsiveness to BCR-crosslinking with anti-IgM (P=0.0015). CD20 levels directly affect BCR-induced calcium flux and the phosphorylation of BCR/PI3K-associated molecules (LYN, SYK, ERK, GAB1) after BCR-crosslinking. The CXCR4dimCD5brightCD20bright subpopulation contains more proliferative (Ki67+) cells, higher levels of pAKT/pERK/pCD79a (P&lt;0.001), and their gene expression signature (NGS Illumina) is significantly enriched for genes involved in BCR and MAPK signaling, migration, and actin cytoskeleton organization (P&lt;0.0001). Finally, we have shown that rituximab primarily and potently eliminates the CXCR4dimCD5brightCD20bright CLL cells (P&lt;0.0001). Overall, rituximab was ~9-fold more efficient in eliminating CXCR4dimCD5brightCD20bright CLL cells than CXCR4brightCD5dimCD20dim cells (P=0.03) during FCR therapy in vivo. Altogether, we described that higher CD20 expression supports BCR signaling and contributes to the activated phenotype and aggressiveness of an intra-clonal subpopulation of CXCR4dimCD5brightCD20bright cells. This is a first mechanistic explanation of CD20 function in CLL cells. Additionally, it is tempting to speculate that rituximab&apos;s clinical success is at least partially attributed to the preferential elimination of the intra-clonal proliferative subpopulation of BCR-proficient CLL cells.

Název v anglickém jazyce

CD20 supports BCR signaling in an intra-clonal aggressive chronic lymphocytic leukemia subpopulation of cells and rituximab primarily targets these BCR-profıcient B cells in vivo

Popis výsledku anglicky

The hallmark of chronic lymphocytic leukemia (CLL) cells is their re-circulation between peripheral blood and immune niches to obtain pro-proliferative and pro-survival signals. CLL cells that have recently exited the immune niches to the peripheral blood are characterized by low cell-surface levels of chemokine receptor CXCR4 and high levels of activation molecule CD5. These CXCR4dimCD5bright CLL cells have a ~2-fold higher CD20 expression due to the activation of the CXCR4/SDF-1 axis (Pavlasova et al., Blood, 2016). We hypothesized that CD20 up-regulation in the context of a microenvironment is required for some functional regulation. We hypothesized that CD20 expression is of importance for B-cell receptor (BCR) signaling as we observed that CXCR4dimCD5brightCD20bright CLL cells have also ~2-fold higher surface IgM levels (P&lt;0.0001). This was coupled with higher responsiveness to BCR-crosslinking with anti-IgM (P=0.0015). CD20 levels directly affect BCR-induced calcium flux and the phosphorylation of BCR/PI3K-associated molecules (LYN, SYK, ERK, GAB1) after BCR-crosslinking. The CXCR4dimCD5brightCD20bright subpopulation contains more proliferative (Ki67+) cells, higher levels of pAKT/pERK/pCD79a (P&lt;0.001), and their gene expression signature (NGS Illumina) is significantly enriched for genes involved in BCR and MAPK signaling, migration, and actin cytoskeleton organization (P&lt;0.0001). Finally, we have shown that rituximab primarily and potently eliminates the CXCR4dimCD5brightCD20bright CLL cells (P&lt;0.0001). Overall, rituximab was ~9-fold more efficient in eliminating CXCR4dimCD5brightCD20bright CLL cells than CXCR4brightCD5dimCD20dim cells (P=0.03) during FCR therapy in vivo. Altogether, we described that higher CD20 expression supports BCR signaling and contributes to the activated phenotype and aggressiveness of an intra-clonal subpopulation of CXCR4dimCD5brightCD20bright cells. This is a first mechanistic explanation of CD20 function in CLL cells. Additionally, it is tempting to speculate that rituximab&apos;s clinical success is at least partially attributed to the preferential elimination of the intra-clonal proliferative subpopulation of BCR-proficient CLL cells.

Druh

O - Ostatní výsledky

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů